The Autoimmune Model: CRPS as Existence Proof
Complex regional pain syndrome provides existence proof that a post-trigger condition with pain, autonomic dysregulation, and fatigue can be driven by functional GPCR autoantibodies.
CRPS has functionally validated agonistic Ξ²2-adrenergic and M2 muscarinic autoantibodies (confirmed via cardiomyocyte bioassays β not just ELISA binding). ME/CFS has ELISA-detected autoantibodies against the same receptor targets, but with undetermined functional status β binding is not the same as functional agonism or antagonism. This is the critical distinction: CRPS autoantibodies are proven to be functionally active; ME/CFS autoantibodies are detected but their functional consequences are unproven.
Key divergences: CRPS autoantibodies are functionally agonistic (producing hyperhidrosis, sympathetic overactivity); ME/CFS shows sympathovagal imbalance (activation and suppression in different domains). Both conditions respond to immunoadsorption β but this is equally consistent with shared GPCR-autoantibody pathology or with non-specific IgG removal benefiting different conditions for different reasons. The CRPS comparison demonstrates feasibility (autoantibodies against these receptors can cause chronic illness) but does not establish identity (ME/CFS autoantibodies may have different functional profiles, different target spectra, or different pathogenic significance).
Consequence: CRPS is the strongest βsplittingβ model in the cluster β it shows that even when two conditions target the same receptors, different functional antibody profiles produce different clinical pictures, and a treatment that works for one (immunoadsorption) may or may not work for the other for the same biological reason.